Application of chlorogenic acid in the preparation of drugs for preventing and treating aortic dissection

Abstract

The present invention provides the use of chlorogenic acid in the preparation of a drug for preventing and treating aortic dissection. By establishing a recognized animal disease model, the pharmacological effects of chlorogenic acid are studied, and it is found and verified that chlorogenic acid has the effects of reducing the morbidity and mortality of aortic dissection; slowing down aortic dilation; and protecting the smooth muscle layer. This proves the use of chlorogenic acid in preventing and treating aortic dissection, and provides a solid pharmacodynamic basis for new clinical research and application of the drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to the use of chlorogenic acid in the preparation of drugs for preventing and treating aortic dissection. Background Art

[0002] Chlorogenic acid (CGA), a depsipeptide formed by the reaction of caffeic acid and quinic acid, is the primary phenolic compound in honeysuckle. It is produced in the plant via the shikimic acid pathway. CGA is an orally active antioxidant. Its hemihydrate forms needle-shaped crystals and is readily soluble in hot water, ethanol, and propanol. CGA exhibits significant anti-inflammatory, antioxidant, anticancer, and antibacterial properties. Previous studies have shown that CGA can dilate blood vessels, lower blood pressure, and lower blood lipids.

[0003] CGA has excellent anti-inflammatory and antioxidant properties. Studies have shown that CGA can inhibit LPS-induced mammary inflammatory cell infiltration; prevent rheumatoid arthritis and its complications; and alleviate renal damage in rats by inhibiting inflammation and oxidative stress. Pretreatment with CGA can upregulate antioxidant enzymes and inhibit the expression of related inflammatory factors. Furthermore, due to the close connection between inflammation and oxidative stress, CGA can activate Nrf2 in PC12 cells by scavenging ROS and restoring mitochondrial function, thereby inducing the expression of antioxidant enzymes.

[0004] CGA also plays an important role in lowering blood sugar and blood lipids. It fights obesity by inhibiting the increase of fat and free fatty acids, while reducing total cholesterol and low-density lipoprotein levels, increasing high-density lipoprotein levels, and improving dyslipidemia. Studies have shown that CGA can improve endothelial cell function through anti-inflammatory / antioxidant effects and inhibition of angiotensin-converting enzyme. CGA has been widely studied in the treatment of cardiovascular diseases: CGA can inhibit hypochlorous acid-induced oxidative stress in endothelial cells, improve in vitro angiogenesis by increasing the levels of NO and heme oxygenase-1, and reduce oxidative stress damage to endothelial cells; in addition, CGA alleviates ox-LDL-induced endothelial oxidative stress and mitochondrial dysfunction by activating SIRT1 and regulating the AMPK / PGC-1 signaling pathway.

[0005] Aortic dissection (AD) is a serious cardiovascular emergency. It occurs when a rupture in the intima of the arterial wall allows blood to enter the arterial wall, forming a hematoma and further separating the aortic intima and media. The recognized cause is structural abnormalities and hemodynamic abnormalities in the aortic media itself. High-risk groups include those with hypertension, older age, aortic atherosclerosis, and inherited vascular diseases.

[0006] Aortic dissection is a sudden and severe disease that is incurable once it develops, and has become a global challenge in the cardiovascular field. Compared with healthy individuals, patients with aortic dissection have severe dysfunction of aortic smooth muscle cells, including impaired barrier and mitochondrial function, and inflammation is common in patients with aortic dissection. While CGA is currently crucial for both vascular and cardiac protection, its role in aortic dissection remains underdeveloped and warrants further investigation. Summary of the Invention

[0007] In view of this, the present invention aims to propose the use of chlorogenic acid in the preparation of drugs for preventing and treating aortic dissection, so as to solve the problems existing in the above-mentioned prior art.

[0008] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0009] In a first aspect, the present invention provides the use of chlorogenic acid in the preparation of a drug for preventing and treating aortic dissection. The structure of the chlorogenic acid is shown in Formula I below:

[0010]

[0011] Furthermore, the chlorogenic acid is the only active ingredient.

[0012] Furthermore, the application includes at least one of the following:

[0013] (1) Application in the preparation of a drug for reducing the morbidity and mortality of aortic dissection;

[0014] (2) Application in the preparation of drugs for repairing damaged aortic walls;

[0015] (3) Application in the preparation of drugs for slowing down aortic dilatation;

[0016] (4) Application in the preparation of drugs for protecting the elastic structure of the smooth muscle layer;

[0017] (5) Application in the preparation of drugs for restoring the elastic phenotype of smooth muscle cells.

[0018] Furthermore, the smooth muscle layer is a vascular smooth muscle layer; preferably, an arterial smooth muscle layer; and more preferably, an aortic smooth muscle layer.

[0019] Furthermore, the daily dosage of chlorogenic acid does not exceed 15 mg / kg; preferably 1-12 mg / kg; more preferably 2-10 mg / kg, for example, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg. These dosages can vary depending on the patient's needs, the severity of the condition being treated, and the compound used. Generally, treatment is started with a smaller dose that is less than the optimal dose of the compound, and thereafter, the dose is increased in small amounts to achieve the optimal effect. For convenience, the total daily dose can be further divided into divided doses within a day if necessary.

[0020] Furthermore, the aortic dissection includes acute aortic dissection or repair aortic dissection.

[0021] In a second aspect, the present invention provides a pharmaceutical preparation for preventing and treating aortic dissection, wherein the active ingredient of the pharmaceutical preparation includes chlorogenic acid, and the structure of the chlorogenic acid is shown in the following formula I:

[0022]

[0023] Furthermore, the chlorogenic acid is the only active ingredient.

[0024] Furthermore, the pharmaceutical preparation also includes pharmaceutically acceptable excipients.

[0025] Furthermore, the excipients include: at least one of a diluent, a binder, a wetting agent, a lubricant, a disintegrant, a solvent, an emulsifier, a solubility aid, a preservative, a pH regulator, an osmotic pressure regulator, a surfactant, a coating material, an antioxidant or a buffer.

[0026] Furthermore, the pharmaceutical preparation includes a clinically acceptable oral preparation, injection preparation or inhalation preparation.

[0027] Furthermore, the pharmaceutical preparation includes at least one of powder, granules, pills, capsules, tablets, injections, powder injections, lyophilized agents, and aerosols.

[0028] Furthermore, the administration route of the pharmaceutical preparation includes at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration or aerosol administration.

[0029] For preparing pharmaceutical formulations suitable for the present invention, pharmaceutically acceptable carriers can be either solid or liquid.

[0030] Solid form preparations include powders, granules, pills, capsules, and tablets. Solid carriers can be one or more substances that also act as diluents, flavorings, solubilizers, lubricants, suspending agents, adhesives, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary adhesive properties in an appropriate ratio and compressed into the desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc.

[0031] Liquid preparations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as water-polyethylene glycol solutions.

[0032] Therefore, the medicaments used in the present invention can be formulated into a preparation for parenteral administration (e.g., injection, such as bolus injection or continuous infusion), and can be presented in the form of a unit dose in ampoules, prefilled syringes, small-volume infusion bags, or multi-dose containers together with added preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and can contain formulation ingredients such as suspending agents, stabilizers, and / or dispersants. In addition, the active ingredient can be in the form of a powder, which can be obtained by aseptic isolation of a sterilized solid or lyophilization from a solution, for reconstitution with a suitable carrier such as sterile, pyrogen-free water before use.

[0033] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding colorants, flavorings, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water containing a viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0034] Also included are solid preparations designed to be converted into liquid preparations for oral administration shortly before use. Such liquid preparations include solutions, suspensions, and emulsions. In addition to the active ingredient, such preparations may contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0035] Respiratory administration can also be achieved by aerosols, wherein the active ingredient is contained in a pressurized package together with a suitable propellant, and suitable propellants include fluorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. Aerosols can also suitably contain surfactants, such as lecithin. The dosage of the medicine can be controlled by a metering valve.

[0036] Alternatively, the active ingredient may be in the form of a dry powder, for example a powder mixture of chlorogenic acid and a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier may conveniently form a gel in the nasal cavity. The powder composition may be in the form of a unit dose, for example, in capsules or cartridges (e.g., gelatin capsules or cartridges), or in blister packs for administration of the powder via an inhaler.

[0037] Alternatively, when desired, compositions adapted for sustained release of the active ingredient may be employed.

[0038] Compared with the prior art, the use of chlorogenic acid in the preparation of drugs for preventing and treating aortic dissection has the following advantages:

[0039] (1) The present invention, through the study of the pharmacological effects of chlorogenic acid, discovered and verified the use of chlorogenic acid in preventing and treating aortic dissection. Chlorogenic acid has a significant effect in improving aortic dissection, providing a solid pharmacodynamic basis for new clinical research and applications of the drug. The drug has broad market prospects after development, and also provides an example for the medicinal use of classic health products and "new uses of old drugs";

[0040] (2) The present invention establishes a mature animal disease model of aortic dissection, providing a solid foundation for subsequent drug development. Based on the established animal disease model, the present invention discovers and verifies the therapeutic and preventive effects of chlorogenic acid in improving the prognosis of aortic dissection.

[0041] (3) The present invention establishes a recognized animal disease model, and comprehensively studies the role of chlorogenic acid in reducing the mortality rate of aortic dissection from multiple indicators such as the pathological morphology of the aorta, pathological sections of the lesion site, Masson staining, and comparison of mouse survival rates, thereby providing a solid scientific basis for the clinical application of the drug.

[0042] (4) The experimental results of the present invention show that chlorogenic acid has the effect of reducing the morbidity and mortality of aortic dissection; chlorogenic acid has the effect of slowing down aortic dilation. These results prove that chlorogenic acid has a protective effect on aortic dissection. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The accompanying drawings, which constitute part of the present invention, are provided to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an undue limitation of the present invention. In the accompanying drawings:

[0044] Figure 1 This is a schematic diagram of the animal experiment process according to an embodiment of the present invention, where the horizontal axis represents the number of intervention days;

[0045] Figure 2This is a schematic diagram of the mouse survival curve according to an embodiment of the present invention;

[0046] Figure 3 This is a schematic diagram of mouse cardiac ultrasound according to an embodiment of the present invention;

[0047] Figure 4 This is a schematic diagram of the maximum diameter of the mouse aorta according to an embodiment of the present invention;

[0048] Figure 5 This is a schematic diagram of the incidence of aortic dissection in mice according to an embodiment of the present invention;

[0049] Figure 6 Schematic diagram of the mouse pathological staining results described in an embodiment of the present invention. DETAILED DESCRIPTION

[0050] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0051] The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with embodiments.

[0052] The present invention uses C57BL / 6J mice as experimental subjects and uses chlorogenic acid to intervene in aortic dissection-induced mice for animal experiments.

[0053] (1) Experimental materials

[0054] Animal experiment groups: 3-week-old mice were divided into control group (hereinafter referred to as control group) with 12 mice; BAPN + chlorogenic acid intervention group (hereinafter referred to as intervention group) with 12 mice; BAPN-induced dissection group (hereinafter referred to as dissection group) with 12 mice;

[0055] BAPN feed: Weigh BAPN powder according to the proportion of 0.4% by weight;

[0056] Preparation of chlorogenic acid: Weigh the chlorogenic acid powder and calculate the daily gavage dose (H2O) based on the daily gavage dose of 100 μL per mouse. Dissolve the weighed chlorogenic acid powder in 50 μL DMSO, sonicate evenly, then add an appropriate amount of distilled water to dilute and store at -20°C.

[0057] (2) Experimental methods

[0058] like Figure 1As shown in Table 1: The control group was fed a normal diet for 21 consecutive days. The intervention and dissection groups were fed a diet containing 0.4% BAPN, mixed with BAPN powder. The intervention group also received chlorogenic acid powder dissolved in DMSO and diluted with water at a dose of 25 mg / kg / day, with 100 μL per mouse administered via gavage daily for 21 days. During the dosing period, mortality was recorded. After the end of the dosing period, the aortic diameter of the mice was measured, and the formation of aortic dissection was observed after dissection. The incidence rate was also calculated.

[0059] Table 1 Animal experiments on chlorogenic acid intervention in mice with aortic dissection

[0060] Select mouse Mouse age BAPN induction dose Chlorogenic acid intervention dose Intervention time C57 3week 0.4％ 25mg / kg / day 21d

[0061] The present invention establishes a recognized animal disease model of aortic dissection, namely, 3-week-old C57BL / 6J mice are fed a feed containing 0.4% β-aminopropionitrile (BAPN) for 21 days to establish a model, causing damage to the cross-linking of elastic fibers in the aortic wall, leading to the formation of aortic dissection aneurysms, simulating clinical aortic dissection injuries. The model was successfully established based on multiple indicators such as the pathological morphology of the aorta, pathological sections of the lesion site, and Masson staining, and can be used to verify the efficacy of chlorogenic acid.

[0062] (3) Evaluation of pathological indicators in animal experiments

[0063] like Figure 2 As shown in the figure, by counting the death time of dissection in different groups of mice, an overall survival curve was drawn up and statistical analysis was performed as of 21 days. The results showed that the survival rate of mice in the intervention group was significantly higher than that in the dissection group, proving that chlorogenic acid intervention significantly reduced the mortality rate of mice with aortic dissection model.

[0064] The animal experiment was induced to 21 days, and the surviving mice were subjected to aortic ultrasound experiments. The intervention effect of chlorogenic acid was evaluated by measuring the maximum diameter of the aorta and performing statistical analysis. The results are as follows Figure 3 and Figure 4 As shown, *** indicates p < 0.001. The results show that the maximum diameter of the aorta dilation in the intervention group (1.45 mm) was significantly smaller than that in the dissection group (1.74 mm) and the control group (1.55 mm). Chlorogenic acid intervention significantly reduced the dilation of the aorta in the model mice.

[0065] like Figure 5As shown in the figure, after echocardiography, mice were sampled and the number of aortic dilatation in different groups was counted. The incidence of aortic dissection in different groups was calculated, and then graphed and statistically analyzed. The red color in the figure represents the number of mice that died from aortic dissection rupture, the blue color represents the number of mice that developed aortic dissection but did not die from aortic dissection, and the black color represents the number of mice that did not develop aortic dissection. The results showed that the probability of aortic dissection and death from aortic dissection rupture in the intervention group was significantly lower than that in the dissection group. Chlorogenic acid intervention reduced the incidence of aortic dissection in the model mice.

[0066] Figure 6 Figure 2 shows the pathological staining results of the aortas of mice in each experimental group, including Masson's stain, Evans blue stain, and elastic fiber stain. These stains indicate the severity of aortic dissection. In the dissection group, elastic fiber staining revealed rupture and dissolution of the elastic lamina in the smooth muscle layer. Masson's staining indicated that smooth muscle cells secreted more inelastic collagen fibers in response to the dissection, impairing aortic elasticity. Evans blue staining revealed extensive mucin deposition in the smooth muscle layer. These pathological staining results indicate that in the aortic dissection model, the structure and function of the vascular smooth muscle layer are impaired, the elastic phenotype is lost, and degenerative remodeling of the aortic wall occurs. Compared with the dissection group, the chlorogenic acid treatment group showed significantly reduced collagen and proteoglycan deposition in the smooth muscle layer and less rupture of the elastic fiber lamina. These results suggest that chlorogenic acid treatment can mitigate the progression of aortic dissection by ameliorating structural and functional damage to the smooth muscle layer and restoring the elastic phenotype of smooth muscle cells.

[0067] According to the results of animal experiments, the incidence and mortality of aortic dissection in mice with aortic dissection model were significantly reduced by gavage intervention of chlorogenic acid. Ultrasound results showed that chlorogenic acid intervention alleviated the expansion of the aortic diameter of model mice. The above pathological indicators indicate that chlorogenic acid intervention effectively alleviated the occurrence and development of aortic dissection in mice.

[0068] The embodiments described above are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work shall fall within the scope of protection of the present invention.

Claims

1. Use of chlorogenic acid in the preparation of a drug for preventing aortic dissection, characterized in that: The structure of chlorogenic acid is shown in Formula I below: 。

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